Background, Incidence, Prevalence

Congenital adrenal hyperplasia (CAH) refers to a group of autosomal recessive disorders in which genetic enzyme deficiencies impair normal steroid synthesis. The production of cortisol in the zona fasciculata of the adrenal cortex occurs in five major enzyme-mediated steps, and deficiency in any one of these leads to CAH. The most common form is 21-hydroxylase deficiency (21-OHD), which accounts for over 90% of CAH cases. Impaired cortisol synthesis, the common feature to all forms of CAH, leads to chronic elevation of adrenocorticotropic hormone (ACTH) and overstimulation of the adrenal cortex, resulting in adrenal hyperplasia. Impaired enzyme function at each step of adrenal cortisol biosynthesis leads to an increase in precursors and deficient products. The clinical and hormonal findings of five forms of CAH are summarized in Table 14.1 . This chapter will focus on CAH owing to 21-OHD, the most frequent form of CAH.

Data from nearly 6.5 million newborn screens worldwide for 21-hydroxylase deficiency indicate that classical CAH occurs in 1:13,000 to 1:15,000 live births. Nonclassical 21-OHD CAH (NC21-OHD) is more common. The incidence of NC21-OHD in the heterogeneous population of New York City is one in 100, making NC21-OHD one of the most frequent recessive disorders in humans. NC21-OHD is particularly frequent in Ashkenazi Jews, in whom one in three are carriers of the allele, and one in 27 are affected with NC21-OHD. Steroid 11 deficiency (11-OHD) is the second most common cause of CAH, accounting for 5–8% of all cases. It occurs in one in 10,000 live births in the general population and is more common in some populations of North African origin. In Moroccan Jews, for example, the disease incidence of 11-OHD was initially estimated to be one in 5000 live births; subsequently, it was shown to occur less frequently, but remains more common in Moroccan Jews than in other populations. 17α-Hydroxylase deficiency is found to be common in Mennonite descendants of Dutch Frieslanders and the Brazilian population. The disease incidence of congenital lipoid adrenal hyperplasia is shown to be common in Japan and Korea. The other forms are considered rare diseases, and the incidence is unknown in the general population.

A very rare form of CAH not included in this table is cytochrome P450 oxidoreductase deficiency. It is characterized by partial, combined deficiencies of P450C17 (17α-hydroxylase), P450C21 (21-hydroxylase), and aromatase. Affected girls are born with ambiguous genitalia, indicating intrauterine androgen excess. However, virilization does not progress after birth. The 17-hydroxyprogesterone levels are elevated, as in 21-hydroxylase deficiency, while androgen levels are low; cortisol may be normal but is poorly responsive to ACTH. Conversely, affected boys may be born undervirilized, owing to 17α-hydroxylase deficiency. Boys and girls can also present with bone malformations, resembling a pattern seen in patients with Antley–Bixler syndrome.

Steroid 21 Hydroxylase Deficiency (21-OHD)

CAH owing to 21-OHD is divided into classical and nonclassical forms. Classical CAH is further divided into salt-wasting (SW) and simple-virilizing (SV) forms. The SW form is the most severe form of CAH and is characterized by inadequate aldosterone synthesis, which places patients at risk for SW crises, whereas the SV form is distinguished by the ability to conserve salt. Both the SW and SV forms result in genital ambiguity in the female. Females affected with classical forms of CAH are born with genital ambiguity termed “46XX, disorder of sex development.” In 21-OHD, the precursors to the 21-hydroxylase enzyme are shunted into the androgen pathway. Virilization of the female genitalia begins in utero as a result of fetal adrenal androgen production. Males do not exhibit genital ambiguity because the major source of androgens in males is the testes, not the adrenals. The nonclassical form of CAH causes postnatal symptoms of hyperandrogenism that may present any time after birth, including adulthood. Table 14.2 summarizes the main clinical characteristics of all forms of 21-OHD CAH.

In all three forms of 21-OHD CAH, both affected males and females experience the effects of postnatal hyperandrogenism unless treatment intervenes. These hyperandrogenic symptoms include premature development of pubic and axillary hair, frontal hair loss, severe acne, advanced somatic and epiphyseal maturation and induced central precocious puberty (a condition in which puberty develops unusually early or rapidly). Early epiphyseal maturation may lead to compromised final adult height. Milder symptoms and/or later presentation are typical in nonclassical 21-OHD CAH owing to genetic mutations associated with less severe enzymatic defects. A synthetic ACTH stimulation test can differentiate 21-OHD from other forms of CAH. A logarithmic nomogram was developed to provide hormonal standards for diagnosis and further assignment of the 21-OHD type by relating baseline to ACTH-stimulated serum concentrations of 17-OHP (see Fig. 14.1 ).

17-OHP nomogram for the diagnosis of steroid 21-hydroxylase deficiency (60-min cotrosyn stimulation test).

The data for this nomogram were collected between 1982 and 1991 at the Department of Pediatrics, the New York Hospital-Cornell Medical Center, New York.